Location of Workgroup

H&E staining of the spleen of an immunodeficient humanized mouse (left). Immunostaining with an anti-human nuclei antibody in the same spleen, showing the distribution of human cells (right picture, arrows)

Preclinical Safety and Toxicology

Objectives

In regards to the fast growing social and clinical importance of stem cell research and regenerative medicine, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) aims to become a competent partner for non-clinical safety and toxicology research of Advanced Therapy Medicinal Products (ATMPs) in particular for cell –based therapeutics. Therefore, we will expand our services in stem cell toxicology according to the authority guidelines, in order to enable cell-based therapeutics to reach the clinical phase.

Research Focus

Service Unit:The Fraunhofer ITEM in Hannover is specialized in developing product-specific testing strategies for pre-clinical testing of non-biologics and biologics, including ATMPs. The basic requirements for the registration of biopharmaceuticals including human cell-based medical products, such as iPSCs, for the European market are regulated by the European Medicines Agency (EMA) Commission Directive 2001/83/EC. With their “guideline on human cell-based medicinal products” EMA takes into account that these human cell-based products are heterogeneous regarding origin, type of cells and complexity and that conventional non-clinical pharmacology and toxicology studies may not be appropriate. Therefore, for every new, innovative human cell-based medicinal products, a specific strategy for pre-clinical testing has to be developed and should be presented to and discussed with the drug registration authorities at an early time point. Fraunhofer ITEM provides support in each aspect of pre-clinical testing, from consulting up to set-up, validation and performance of complex assays, all the way ensuring regulatory acceptance of the development strategy. Further effort has to be made to get into regenerative science. Fraunhofer ITEM has a long-standing tradition in pre-clinical testing of new drugs including safety-relevant studies according to the principles of GLP. Fraunhofer ITEM holds a respective GLP certificate.

Research: Transplantation of multipotent hematopoietic stem cells is successfully supplied for treatment of blood derived diseases, like leukemia or sickle cell anemia. However, the number of compatible donors is limited and complications with graft-versus-host (GvHD) or host-versus-graft disease (HvGD) is still an unresolved issue. To overcome these hurdles, researchers are investigating protocols for efficient expansion of isolated hematopoietic stem cells (HSC) as well as for de novo generation of HSC in vitro since decades.

Positioned within the REBIRTH network, the Institute of Experimental Hematology (MHH), Institute for Laboratory Animal Science (MHH) and Fraunhofer ITEM, started a collaborative project investigating teratoma formation with pluripotent stem cells, their potential to differentiate into hematopoietic cells and resulting effects on the host organism. This model will help to identify responsible key players for early human hematopoiesis regarding cell environment of hematopoiesis including cellular components and cell interactions. Mediated insights offer opportunity to improve and establish in vitro protocols for generation and proliferation of human HSC. Valid protocols perspectively enable the installation of stem cell banks, covering most immunotypes, which can be used for transplantation needs.

A core area of our research is the detection and the immunohistochemical demonstration of HSC and iPSC in tissues and whole organ slices of laboratory animals, also if the number of cells distributed throughout the body is low. For this issue a broad spectrum of antibodies could be established at Fraunhofer ITEM. For safety toxicology and in regard of registration purposes, histopathology and immunohistochemistry were performed under GLP-conditions.

Teaching

Seminars entitled »Basics of pathology in laboratory rodents I« for PhD-students of the programme PhD Reg Sci (REBIRTH/HBRS) were performed in November 2014 and 2015. Additionally, we participate in the training of students from MHH, TiHo (PhD students of the HGNI) and Leibniz University and further supervise and co-supervise several internships, diploma theses and Ph.D. theses.